Shinichi Makita

Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma.

B‐cell non‐Hodgkin lymphoma (B‐NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti‐CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B‐NHL. Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B‐cell leukemia and lymphoma. Recently, several clinical trials have shown remarkable efficacy of anti‐CD19 CAR T‐cell therapy, not only in B‐acute lymphoblastic leukemia but also in B‐NHL. Nonetheless, there are several challenges to overcome before introduction into clinical practice, such as: (i) further refinement of the manufacturing process, (ii) further improvement of efficacy, (iii) finding the optimal infusion cell dose, (iv) optimization of lymphocyte‐depleting chemotherapy, (v) identification of the best CAR structure, and (vi) optimization of toxicity management including cytokine release syndrome, neurologic toxicity, and on‐target off‐tumor toxicity. Several ways to solve these problems are currently under study. In this review, we describe the updated clinical data regarding anti‐CD19 CAR T‐cell therapy, with a focus on B‐NHL, and discuss the clinical implications and perspectives of CAR T‐cell therapy.

Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma

Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma

Mogamulizumab for the treatment of T-cell lymphoma

ABSTRACT Introduction: T-cell lymphoma is a relatively rare hematologic malignancy that accounts for 10–20% of non-Hodgkin lymphomas. Treatment strategies for T-cell lymphomas are different from that for B-cell lymphomas and have poor prognoses. Among various subtypes of T-cell lymphomas, adult T-cell leukemia-lymphoma (ATL) has the worst prognosis. To achieve further improvement in the treatment outcome of T-cell lymphomas, several novel agents such as brentuximab vedotin, lenalidomide, romidepsin, and pralatrexate are actively being studied. Mogamulizumab, an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, is one of the promising agents for CCR4-positive T-cell lymphomas, especially for ATL. Areas covered: First, basic information about the current treatment strategy of T-cell lymphomas including ATL is described. Then, the authors discuss the current clinical development of mogamulizumab and its clinical implications for T-cell lymphomas. Expert opinion: Mogamulizumab has potent clinical efficacy against CCR4-positive T-cell lymphomas, especially against ATL. Among various toxicities associated with mogamulizumab, skin eruptions are the most significant. Although there are several effective competitors, mogamulizumab has a unique mechanism and is expected to be a key agent for treating CCR4-positive T-cell lymphomas, especially ATL.

Clinicopathological features of histological transformation from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue to diffuse large B-cell lymphoma: an analysis of 467 patients

This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation (HT) from extranodal marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma) to diffuse large B‐cell lymphoma (DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited‐stage diseases (n = 385) and 16% in advanced‐stage diseases (n = 56) (P = 0·02). The median time to HT was 48 months (range, 4–139). Five‐year progression‐free survival (PFS) and overall survival (OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B‐cell (GCB)/non‐GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB‐type DLBCLs exhibited CD10−, BCL6+ and MUM1− immunophenotypes; the remainder had CD10+ immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS (P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced‐stage cases, risk of HT was relatively high and prognosis was unfavourable.

Histopathological Characteristics of Lymphomas in the Upper Aerodigestive Tract. A Single-Institute Study in Japan.

We analyzed the histopathological characteristics of lymphomas biopsied from the upper aerodigestive tract between 2000 and 2014 at the National Cancer Center Hospital in Japan. Of a total of 309 consecutive cases, the following incidences were observed: mature B-cell neoplasms, 77% (n = 239); mature T- and NK-cell neoplasms, 20% (n = 63); classical Hodgkin lymphomas, 0.7% (n = 2); and lymphoblastic lymphomas, 2% (n = 5). Lymphomas were most frequently (57%) detected in the oropharynx. The majority of cases (89%) were mature B-cell neoplasms (diffuse large B-cell lymphoma, 60%; follicular lymphoma, 10%), and 10% of cases were mature T-cell neoplasms. Six cases of plasma cell neoplasm (4 primary and 2 secondary involvement) and 2 cases of plasmablastic lymphoma in the upper aerodigestive tract were observed. Two out of 3 cases of extraosseous plasmacytoma with available biopsy material were positive for EBER1. All 3 patients received irradiation and achieved complete response; 1 had not relapsed after 17 months and the remaining 2 relapsed as plasma cell myeloma and solitary plasmacytoma of the bone. Of 47 extranodal NK/T-cell lymphoma, nasal-type cases in the upper aerodigestive tract, 38 (81%) were present in the sinonasal region and the remaining 9 (19%) were in the oropharynx (n = 4), nasopharynx (n = 3), and oral cavity (n = 2). In conclusion, since both primary lymphoma and secondary involvement of lymphoma are often diagnosed using biopsied materials from the upper aerodigestive tract, pathologists and hematologists should recognize the characteristics of lymphoma in this tissue.

Clinicopathological features of classical Hodgkin lymphoma in patients ≥40 years old, with special reference to composite cases

OBJECTIVE Classical Hodgkin lymphoma shows a peak incidence at 15-35 years, and a second peak in elderly patients; however, pathological characteristics of elderly patients with classical Hodgkin lymphoma have not been analyzed enough. METHODS In a total of 154 patients with classical Hodgkin lymphoma, we analyzed the clinicopathological characteristics of classical Hodgkin lymphoma patients aged ≥ 40 years old, with special reference to the incidence, histopathology and outcome of patients with composite classical Hodgkin lymphoma. RESULTS Of 154 patients with classical Hodgkin lymphoma, 50 (32%) were ≥ 40 years old. The 5-year progression-free and overall survival rates were 59 and 86%, respectively. Thirty-eight patients (76%) had non-composite classical Hodgkin lymphoma, 10 patients (20%) had composite (6 simultaneous and 4 consecutive) classical Hodgkin lymphoma and B-cell non-Hodgkin lymphoma and 2 patients (4%) had methotrexate-associated classical Hodgkin lymphoma. Of 10 patients with composite classical Hodgkin lymphoma, composite lymphomas were detected throughout the staging procedure of the upper gastrointestinal tract or bone marrow in 4 patients. Fluorescence in situ hybridization revealed that the composite lymphomas of 4, 1 and 5 patients were related, unrelated and of unknown correlation status, respectively. The treatments after the diagnosis of a classical Hodgkin lymphoma component varied, and three patients died of lymphoma. CONCLUSIONS We found that the incidence of composite classical Hodgkin lymphoma in patients ≥ 40 years old was 20%. Correct diagnosis and optimal treatment for patients with composite classical Hodgkin lymphoma and B-cell non-Hodgkin lymphoma is highly important in this patient population.

Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma

We aimed at investigating the relationship between classical Hodgkin lymphoma (cHL), primary mediastinal large B‐cell lymphoma (PMBL), and gray zone lymphoma (GZL) with intermediate characteristics between cHL and PMBL, from the perspective of the aberration in programed cell death 1 and the programed death ligands (PDLs) network.

Clinical Features and Current Optimal Management of Natural Killer/T-Cell Lymphoma

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), is a rare subtype of non-Hodgkin lymphoma, and its treatment outcome was previously poor. Novel treatment strategies have improved the outcomes of ENKL remarkably in the last decade. Nowadays, patients with localized nasal ENKL are recommended treatment with concurrent chemoradiotherapy, and their 5-year overall survival rate is approximately 70%. In patients with advanced or relapsed/refractory disease, the efficacy of l-asparaginase-containing therapy has been confirmed. However, there still remain unmet needs in the treatment of ENKL. Continued efforts should be made to further improvements in the treatment of ENKL.

Impact of the double expression of MYC and BCL2 on outcomes of localized primary gastric diffuse large B-cell lymphoma patients in the rituximab era.

Diffuse large B-cell lymphoma (DLBCL) is a common subtype of primary gastric lymphoma, accounting for 50–60% of cases.1 Prior to the rituximab era, a Japanese phase II trial evaluated three courses of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP), followed by 40.5 Gy of involved field radiotherapy (IFRT) for localized (stage I, II1 based on the Lugano Staging System for Gastrointestinal Lymphoma2) primary gastric DLBCL (PG-DLBCL) and the study yielded good therapeutic results.3 Rituximab plus CHOP (R-CHOP) therapy has been shown to improve the prognosis of DLBCL patients over that of patients treated with CHOP.4, 5 The efficacy of three cycles of R-CHOP followed by IFRT for localized DLBCL was evaluated in a phase II trial by the Southwest Oncology Group and also showed favorable results.6 On the basis of these findings, a rituximab-containing regimen, particularly three cycles of R-CHOP followed by IFRT, is regarded as one of the standard therapies for localized DLBCL including PG-DLBCL. Recent studies demonstrated that the double rearrangement (double hit) of the MYC and BCL2 genes and the double expression of the MYC and BCL2 proteins were associated with a poor prognosis for patients with nodal DLBCL.7, 8, 9, 10 However, the clinical impact of the double expression of MYC and BCL2 on PG-DLBCL remains unknown. We retrospectively analyzed patients with localized PG-DLBCL who were initially treated with a rituximab-containing regimen, with a focus on the status of MYC and BCL2.

Paraneoplastic Pemphigus Associated with B-cell Chronic Lymphocytic Leukemia Treated with Ibrutinib and Rituximab

Paraneoplastic pemphigus (PNP) is a severe autoimmune blistering disease associated with an underlying malignancy, and its prognosis is poor. We herein report the first patient with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL)-associated PNP successfully treated with the Brutons tyrosine kinase inhibitor ibrutinib and rituximab. Although his PNP lesions did not improve with ibrutinib monotherapy, the combination of ibrutinib and rituximab was effective against B-CLL/SLL-associated PNP. This case suggests that ibrutinib plus rituximab may be a potent therapeutic option for B-CLL/SLL-associated PNP that is hard to control with ibrutinib alone.